Description: Project Summary and Relevance Intracranial aneurysms affect a substantial portion of the adult population. They rarely rupture, but intracranial hemorrhage due to a ruptured brain aneurysm has devastating effects with high mortality and disability rates. Since the risk of treatment may exceed the natural risk of rupture, there is an urgent need for a reliable method to identify fragile aneurysms at risk of rupture that require immediate treatment and avoid unnecessary treatment in others. Prior work has largely focused on looking for correlations between rupture and clinically attainable quantities such as geometry, hemodynamics and patient characteristics. However, to date, these efforts have been promising but have not reached their full potential. Our group and others believe this is because the flow dynamics play more than one role in wall degradation and further there are multiple modes of wall failure. Therefore, it is extremely challenging to identify correlations without further information about the wall itself. The proposed research is innovative in our opinion because it seeks to shift the way aneurysm pathology is studied by turning the focus to the clinically relevant vulnerable aneurysm wall and by directly assessing the possibly multiple mechanisms by which hemodynamics alters the wall and studying the mechanisms of structural failure. This approach is possible because we have spent the prior R21 period i) building a collaborative team of world leaders with diverse skills in aneurysm research, ii) acquiring all needed IRB and MTA documents that will enable us to obtain over 350 IA domes during this program, and iii) developing the numerous innovations in methodology that take advantage of access to an array of important experimental facilities. Understanding the factors that discriminate between robust aneurysm walls with well-organized collagen fibers and vulnerable or fragile aneurysm walls with diverse changes to the collagen architecture is essential for effective prediction of aneurysm vulnerability and design of treatments to slow or reverse this change. Specifically, the goals of this project are: 1) determine the characteristics of structurally sound aneurysm walls, 2) determine structural causes of aneurysm wall vulnerability, 3) determine the hemodynamic conditions that promote endothelial dysfunction and wall alteration, and 4) develop a framework for assessing risk of wall fragility. The contribution of the proposed work is significant because it will create a paradigm shift in how cerebral aneurysms are studied. The focus on rupture as the end point will be shifted to wall vulnerability using methods we developed during the R21 period. We will use this data, combined with patient characteristics, to develop a framework for assessing risk of wall vulnerability. These results will provide he basis for a larger multi-national trial using our framework for risk stratification. Clinical relevance of the proposed project: The results of this project will be immediately applicable to the clinical practice, in particular we will provide the community with a scale to grade the risk of an aneurysm of having fragile walls. Additionally, these results will guide future research aiming at developing new clinical imaging techniques and/or contrast agents by providing them with wall changes associated with vulnerable walls. Further by understanding the differences between robust and vulnerable walls, we will provide a target for pharmacological therapies directed at harnessing the natural ability of the wall the maintain a robust collagen structure. These advancements will all contribute to the improvement of patient care.